St. Louis, Feb. 25, 2004 — An experimental cross-species transplant to treat
diabetes has passed an early test in rats with better-than-expected results,
suggesting the innovative approach might halt type 1 diabetes while greatly
reducing the risk of rejection.

Scientists at Washington University School of Medicine in St. Louis set up
control and experimental groups of rats with diabetes. The experimental group
received embryonic pig pancreas cell transplants and antirejection drugs to
prevent the rats’ immune systems from destroying the transplants. The control
group received only the transplants and no immune suppression drugs. To the
researchers’ surprise, the control group’s transplants grew unmolested by the
immune system, halting the rats’ diabetes and changing the focus of the study
to transplanting without the need for immune suppression.

“Every once in a while you get lucky, and now we have the possibility of
transplanting these pig cells and not having to worry about rejection,” says
Marc R. Hammerman, M.D., the Chromalloy Professor of Renal Diseases in
medicine and leader of the study.

The results appear online and will be published in the April issue of The
American Journal of Physiology-Endocrinology and Metabolism.

Hammerman, an endocrinologist and director of the Renal Division, is a leader
in the emerging field of organogenesis, which is focused on growing organs
from stem cells and other embryonic cell clusters known as organ primordia.
Unlike stem cells, primordia cannot develop into any cell type — they are
locked into becoming a particular cell type or one of a particular set of
cell types that make up an organ.

In multiple groups of diabetic rats that were unable to produce their own rat
insulin, Hammerman and Sharon Rogers, research instructor in medicine,
transplanted pig pancreas primordia into the omentum, a membrane that
envelops the intestines and other digestive organs. Within two weeks, the
primordia engrafted and began producing pig insulin.

The pig insulin replaced the missing rat insulin, returning the rats’ blood
glucose to normal levels, an effect that continued for the rest of their
lives. Failure to gain weight, another characteristic symptom of diabetes,
was also reversed following the transplants.

In a final group of transplant recipients, Rogers, Hammerman, Feng Chen,
Ph.D., assistant professor of medicine, and Mike Talcott, D.V.M., director of
veterinary surgical services, showed that pig insulin-producing cells were
present in the omentum and had caused a buildup of fat, a change previously
linked to successful engraftment of pancreatic tissue.

Hammerman had theorized for years that implanting primordia obtained very
soon after organ formation and coaxing the cells into growing into fully
functioning organs inside a transplant recipient might reduce immune system
rejection. However, he admits he is stunned by the new success.

“Conditions that are permissive for transplantation from one species to
another frequently don’t translate to transplants into another species,”
Hammerman says. “But this dramatic elimination of the need for immune
suppression is quite unusual; there’s not a lot of precedent in the
literature for it. So it’s possible that it may also apply in other cross-
species transplants and maybe even in pig-to-human transplants.”

Diabetes in humans is sometimes treated by transplanting human insulin-
producing pancreas cells known as the islets of Langerhans. According to
Hammerman, using embryonic pig cells as the transplant source instead of
human islets circumvents three major difficulties.

“First, there aren’t nearly enough human pancreas organs to go around,”
Hammerman says. “Since pig insulin works fine in humans, if pigs could be
used as donors the shortage would be alleviated.”

Second, islets can only be extracted from the pancreas by mincing the organ
and exposing it to enzymes that break down connective tissue.

“This damages islets,” Hammerman says. “So not all of the transplanted islets
engraft, and many that do engraft die after a period of time.”

Third, islets are composed of mature cells unable to respond to increased
need for their services by dividing and producing more cells. In contrast,
embryonic pancreas cells divide readily in response to such needs, resulting
in a potentially expandable source of insulin.

For reasons not yet understood, the transplanted pancreas cells did not
develop an additional digestive function normally associated with the
pancreas.

“That was another remarkably lucky break,” Hammerman notes, “because only the
endocrine cells are required to treat diabetes. The digestive cells would
have only caused problems.”

If elimination or reduction of immune rejection transfers to pig-to-human
transplants, the technique will defeat or greatly diminish a final formidable
obstacle to treating diabetes with transplants.

“Immunosuppressing a patient introduces a whole new set of dangers and side
effects,” says Hammerman. “Patients with type 1 diabetes have to ask
themselves, would I rather take insulin, or would I rather take all these
immunosuppressive drugs? It’s not the greatest choice in the world.”

The next phase of research will involve pig-to-primate transplants. If those
are successful, then pig-to-human transplant trials can be considered.

Hammerman also is studying the use of kidney primordia from embryonic pigs to
grow new kidneys inside recipients as a treatment for end-stage kidney
failure.